Adrenergic nerve fibers comprise the majority of the postganglionic nerve fibers, having norepinephrine as the primary neurotransmitter. Autonomic nerve impulses induce adrenergic responses in many bodily organs. The responses are varied, including blood vessel constriction, constriction of the stomach, intestinal, and genito-urinary sphincters, bronchial muscle relaxation and increased heart rate.
Agents that block responses to adrenergic nerve activity through interaction with alpha-adrenoceptors are referred to as alpha adrenergic blocking agents. The blocking agents selectively inhibit responses to adrenergic sympathetic nerve activity and to epinephrine and other sympathomimetic drugs. The response to sympathomimetic amines such as norepinephrine and isoproterenol was first used to categorize adrenergic receptors. The alpha receptors are potently affected by norepinephrine and very poorly affected by isoproterenol. On the other hand, the beta receptors are poorly affected by norepinephrine and potently affected by isoproterenol.
Alpha-adrenergic receptors (or alpha adrenoceptors), including the alpha.sub.1 and alpha.sub.2 subtypes, are found in many locations throughout the body. Thus, the alpha-adrenergic blocking agents (alpha-blockers) have been suggested to have, or have a variety of therapeutic uses, including the treatment of prostate and genito-urinary disorders such as benign prostatic hyperplasia (BPH); peripheral vascular disorders, including Raynaud's disease, acrocyanosis, frost bite, acute arterial occlusion, phlebitis, phlebothrombosis, diabetic gangrene, causalgia, shock and pheochromocytoma; hair loss; and hypertension, see Goodman and Gilman, The Pharmacological Basis of Therapeutics 7th Ed, 1985, MacMillan and Co., the contents of which are hereby incorporated by reference.
Although intravenous (i.v.) infusion of alpha blockers and other therapeutic agents is recognized as a superior mode of drug administration due to bypassing hepatic first pass metabolism and maintaining a constant and prolonged drug level in the body, such methods of drug administration require close medical supervision and may necessitate hospitalization. However, the transdermal administration of active agents offers many of the benefits of i.v. infusion, including direct entry of the drug into the systemic circulation and continual release of the drug. Transdermal delivery is also particularly advantageous for drugs having short half-lives, as maintenance of the required blood levels of these drugs required a higher frequency of bolus dose administration of the drug.
Transdermal delivery of active compounds also provides a non-invasive method for the controlled release and delivery of an active agent. This is advantageous as compared to non-controlled release methods, which may result in underdosing or overdosing of the drug. Other advantages of transdermal drug delivery may include reduction in dosing frequency, reduced fluctuation in circulating drug levels, increased patient compliance and convenience, and a more uniform effect. Transdermal delivery also avoids some of the disadvantages associated with oral drug delivery, such as gastrointestinal irritation. However, many drugs have been difficult to administer transdermally, due to the low skin flux or permeation rates of the drug and the amount of drug that must be delivered for therapeutic efficacy.
It would therefore be desirable to administer transdermally a therapeutically effective amount of an alpha adrenoceptor blocker.